Ischemic stroke is the major cause of vascular dementia. Epidemiological studies have suggested a progressive course of dementia after ischemia stroke. Consistently, the preliminary study presented in this application indicates that, following a transient focal cerebral ischemia, rats exhibit a delayed significant decline of cognitive function. Furthermore, a delayed synaptic alternation was indicated in the hippocampus remote to the primary ischemic area. The relatively slow onset of cognitive dysfunction and synaptic alternation in the hippocampus suggest that therapeutic interventions applied after ischemic stroke could prevent progression of vascular cognitive impairment. In this application, we propose to further determine the long-term effects of transient focal cerebral ischemia on various sensorimotor and cognitive functions of rats, and to delineate the neuropathological mechanisms underlying the vascular cognitive impairment in this model with a focus on the hippocampus synaptic alternation, using behavioral, molecular biochemical, and electrophysiological approaches. In addition, the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue will be tested in this experimental model. To achieve this objective, the following aims will be addressed: Specific Aim 1. To characterize vascular cognitive impairment after transient focal cerebral ischemia. In the proposed studies, an extensive behavioral battery will be employed to determine the impact of transient focal cerebral ischemia on long-term sensorimotor functions, cognitive functions, and anxiety-related behavior in a transient middle cerebral artery occlusion model in rats. Specific Aim 2. To determine the mechanisms contributing to the progressive decline of cognitive function after transient focal cerebral ischemia. We will focus on the neuropathological change in hippocampus, which plays a critical role in cognitive function, since delayed synaptic alternation has been identified in this area remote to the primary infarct area after transient middle cerebral artery occlusion in rats. Specific Aim 3. To determine the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue on the progression of vascular cognitive impairment induced by transient focal cerebral ischemia, using behavioral, biochemical, and electrophysiological approaches. Collectively, the studies proposed will provide new insight in the mechanism of vascular dementia and identify potential therapeutic target for the prevention of cognitive decline following cerebral ischemia. PUBLIC HEALTH RELEVANCE: In this application, we propose to determine the long-term effects of transient focal cerebral ischemia on various sensorimotor and cognitive functions of rats, and to determine the neuropathological mechanisms underlying the vascular cognitive impairment in this model with a focus on the hippocampus synaptic alternation, using behavioral, molecular biochemical, and electrophysiological approaches. In addition, the effects of therapeutic intervention with 172-estradiol and a non-feminizing estrogen analogue will be tested in this experimental model. The studies proposed will provide new insight on the mechanism of vascular dementia and identify potential therapeutic target for the prevention of cognitive decline following cerebral ischemia.